'Spiteful' gene manipulation could combat malaria

A new way to make specific genes spread faster through insect populations has been developed, paving the way for novel methods of combating insect-borne diseases such as malaria.

Researchers have genetically engineered flies which only survive to hatch if they inherit a gene that produces a crucial developmental protein. This genetic manipulation could be adapted to make malaria-resistance mutations more prevalent in mosquito populations. But releasing populations of such genetically engineered mosquitoes could prove controversial, they admit.

There are many teams working to develop mosquitoes that cannot pass on the malaria parasite. Such insects are typically engineered to carry an additional gene to make a protein that protects them against the parasite.

But these mosquitoes typically have to expend slightly more energy and nutrients to produce the extra proteins, which could lead to a minor reduction in their lifespan or fertility compared with ordinary mosquitoes. And even a small fitness disadvantage could cause the genetically modified mosquitoes to disappear after a few generations in the wild.

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Bruce Hay at CalTech in Pasadena, California, US, and colleagues believe they have come up with a solution to ensure that modified mosquitoes prevail and make up an increasing proportion of the mosquito population. The team has designed a novel genetic manipulation that ensures only insects with a specific trait survive early development – and they have tested the technique in fruit flies.

Back to front

Under normal circumstances, a female fly will produce a protein called Myd88 and package it into all of her eggs. The Myd88 protein plays a vital role, helping the cells in the fly embryo distinguish between the front and back of the developing insect. Insects that lack this protein never hatch from the egg.

Hay’s team engineered female flies to make a short “micro-RNA” molecule that blocks the production of Myd88. The eggs of these bugs lacked the crucial protein as a result. Embryos resulting from these egg cells died.

But the researchers also put a copy of the Myd88 gene near a special “promoter” sequence of DNA that gets switched on during early embryonic development. So, although the female flies did not pass on the protein, some of their young received a copy of the genetic code instructing them to produce it during early development. In the embryos that inherited the extra copy of the Myd88 gene, this was switched on after fertilization, and development was normal.

This manipulation is now known as a “Medea” element (maternal effect dominant embryonic arrest). They say it is no coincidence that it is named after the Greek mythological figure Medea, who killed her children out of spite when her husband decided to divorce her and take another wife. Hay explains that the “spiteful” Medea gene manipulation in a female fly leads to the death of some of her offspring – those that inherited a copy of the crucial gene.

Lab trials of the technique proved successful. When 25% of the flies started out with this genetic element, 10 to 12 generations later all of the flies carried it.

Abandoned cargo

Hay says that the Myd88 protein is also crucial for mosquito development, so it is possible to adopt this method for mosquitoes. A key future experiment will involve attaching a malaria-resistance gene to the Myd88 code engineered to get switched on in the offspring during early development.

But Hay notes that it is crucial that the anti-malaria genetic “cargo” remain attached&colon; “What you really don’t want is the selfish genetic element to spread without its cargo.” This could have unknown consequences, he fears.

He also says that the idea of releasing genetically modified mosquitoes will probably meet opposition from people who fear it could have unpredictable negative consequences. “Insects don’t respect national boundaries,” he adds, stressing that countries should coordinate their decision about whether or not to release the mosquitoes.

Hay stresses that the use of these mosquitoes could potentially save many people’s lives by stopping the spread of malaria.